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Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness.

ABSTRACT: Hydrogen sulfide (H2S) has long been known as a toxic environmental hazard. Discovery of physiological roles of H2S as a neurotransmitter by Kimura and colleagues triggered an intensive research in the biological roles of H2S in the past decades. Manipulation of H2S levels by inhibiting H2S synthesis or administration of H2S-releasing molecules revealed beneficial as well as harmful effects of H2S. As a result, it is now established that H2S levels are tightly controlled and too much or too little H2S levels cause harm. Nonetheless, translation of sulfide-based therapy to clinical practice has been stymied due to the very low therapeutic index of sulfide and the incomplete understanding of endogenous sulfide metabolism. One potential strategy to circumvent this problem is to use a safe and stable sulfide metabolite that may mediate effects of H2S. Alternatively, endogenous sulfide levels may be controlled using specific sulfide scavengers. In this review article, the role of endogenous H2S production and catabolism will be briefly reviewed followed by an introduction of thiosulfate and H2S scavengers as novel pharmacological tools to control H2S-dependent signaling.

SUBMITTER: Marutani E

PROVIDER: S-EPMC6994583 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness.

Marutani Eizo E Ichinose Fumito F

Intensive care medicine experimental 20200131 1

Hydrogen sulfide (H2S) has long been known as a toxic environmental hazard. Discovery of physiological roles of H2S as a neurotransmitter by Kimura and colleagues triggered an intensive research in the biological roles of H2S in the past decades. Manipulation of H2S levels by inhibiting H2S synthesis or administration of H2S-releasing molecules revealed beneficial as well as harmful effects of H2S. As a result, it is no ...[more]

PMID: 32006269

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Project description:Hydrogen sulfide (H2S), a gaseous signaling molecule, is associated with the development of various malignancies via modulating various cellular signaling cascades. Published research has established the fact that inhibition of endogenous H2S production or exposure of H2S donors is an effective approach against cancer progression. However, the effect of pharmacological inhibition of endogenous H2S-producing enzymes (cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST)) on the growth of breast cancer (BC) remains unknown. In the present study, DL-propargylglycine (PAG, inhibitor of CSE), aminooxyacetic acid (AOAA, inhibitor of CBS), and L-aspartic acid (L-Asp, inhibitor of 3-MPST) were used to determine the role of endogenous H2S in the growth of BC by in vitro and in vivo experiments. An in silico study was also performed to confirm the results. Corresponding to each enzyme in separate groups, we treated BC cells (MCF-7 and MDA-MB-231) with 10 mM of PAG, AOAA, and L-Asp for 24 h. Findings reveal that the combined dose (PAG + AOAA + L-Asp) group showed exclusive inhibitory effects on BC cells' viability, proliferation, migration, and invasion compared to the control group. Further, treated cells exhibited increased apoptosis and a reduced level of phospho (p)-extracellular signal-regulated protein kinases such as p-AKT, p-PI3K, and p-mTOR. Moreover, the combined group exhibited potent inhibitory effects on the growth of BC xenograft tumors in nude mice, without obvious toxicity. The molecular docking results were consistent with the wet lab experiments and enhanced the reliability of the drugs. In conclusion, our results demonstrate that the inhibition of endogenous H2S production can significantly inhibit the growth of human breast cancer cells via the AKT/PI3K/mTOR pathway and suggest that endogenous H2S may act as a promising therapeutic target in human BC cells. Our study also empowers the rationale to design novel H2S-based anti-tumor drugs to cure BC.

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Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness.

Publications

Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness.

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